Lhrh - antagonists in the treatment of fertility disorders

ABSTRACT

A method of treating infertility disorders by 1) administering an LH-RH antagonist, preferably Cetrorelix, in amounts to selectively suppress endogenous LH but not FSH secretion and 2) inducing follicle growth by administration of exogenous gonadotropin. The selective suppression OF LH allows FSH secretion to be at natural level S thereby not affecting individual estrogen development. The LH-RH antagonist can be given as a single or dual subcutaneous dose in the range of 1 mg to 10 mg, preferably 2 mg-6 mg. In multiple dosing posology, LH-RH antagonist can be administered subcutaneously in an amount in the range of 0.1 to 0.5 mg of LH-RH antagonist/day . LH-RH antagonist is applied starting cycle day 1 to 10, preferably on day 4 to 8, and ovulation can be induced between day 9 and 20 of the menstruation cycle by administering rec. LH, native LH-RH, LH-RH agonist or by HCG. In addition rec. LH, native LH-RH or LH-RH agonist can be given to avoid hyperstimulation syndrome and native LH-RH or a LH-RH agonist can be administered to avoid luteal phase stimulation by neutralising the negative effects of HCG.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is based on provisional application Ser. No. 60/011,282 filed Feb. 7, 1996, the content of which is incorporated herein by reference.

FIELD OF THE INVENTION

The field of invention is directed to the use of LHRH-antagonists to treat male and female fertility disorders.

BACKGROUND OF THE INVENTION

The reasons for unsuccessful attempts to establish pregnancy can be attributed equally to male and female fertility disorders. Today many different assisted reproduction techniques are available. These techniques are used to induce multiple and synchronous follicular growth and thereby obtain fertilizable oocytes.

The current standard treatment is to induce multiple follicular development by administering high doses of HMG (Human Menopausal Gonadotropin). This results in ovarian hyperstimulation. Upon reaching a suitable degree of oocyte maturation using these techniques, ovulation is induced by the administration of HCG (Human Chorion-Gonadotropin) in order to obtain a sufficient number of oocytes. During this time, the clinic-infrastructure preparation can begin. Preparation includes recovery of oocytes by abdominal or transvaginal puncture, intracorporal or extracorporal fertilization of oocytes by different techniques and embryo replacement into the uterus. Routinely, beginning pregnancy is supported by additional administrations of HCG or progesterone. Today this treatment is applied to clinical conditions of male and female infertility.

Complications that are frequently observed during the hyperstimulation procedure are:

A: premature surges of luteinizing hormone (LH) at a premature maturation state with a rupture of the follicles that induced a subsequent cancellation of the treatment occurring in about 25% of the patients; and B: ovarian hyperstimulation syndromes induced by exogenous gonadotropins which in severe cases require hospitalization and are life-threatening.

In order to avoid premature LH-surges, today LHRH-agonists are used as a comedication. By continued administration of these drugs, a complete suppression of endogenous gonadotropins is achieved by desensitization of pituitary cells and down-regulation of their receptors. Subsequently, the gonadotropin levels can be controlled by exogenous injection and the pituitary is refractory to the stimulation of LH-release by increasing levels of estradiol. Disadvantages are 1) a long treatment period until the suppression and down-regulation occur; 2) estrogen withdrawal symptoms; 3) disturbance of the normal menstrual cycle; 4) the need for frequent hormone determinations in order to evaluate the time of onset of suppression; and 5) high dose HMG treatment is needed for ovarian stimulation.

The pathogenesis of hyperstimulation syndrome is not completely understood, but is thought to be associated with the use of HCG for ovulation induction and luteal phase support.

One recent approach involves the use of the LHRH antagonist Cetrorelix (INN). In first clinical trials, short term treatment with Cetrorelix resulted in a complete avoidance of premature LH surges during stimulated cycles and the need for HMG. Due to the immediate suppression of gonadotropins by this antagonist, the unwanted stimulatory phase and also the withdrawal of estrogen produced by the agonists was avoided. The duration of treatment was also significantly shortened. In addition, it was shown that a single injection of an antagonist, given in the mid-follicular phase, would adequately suppress premature LH surges.

SUMMARY OF THE INVENTION

Despite the improvements described above, these treatment modalities suffered the drawback of treating the patients with the highest possible dose of exogenous gonadotropins to hyperstimulate multiple follicular development which results in some severe adverse events.

The current invention reduces the severe adverse events, improves patient compliance and reduces costs. Recent data obtained with Cetrorelix also demonstrates additional surprising new advantages for the treatment of male and female infertility.

In animal experiments and clinical studies with Cetrorelix, it was possible to induce an arrest of the normal, unstimulated follicular growth by multiple or single injections. These effects were observed with extremely low dosage levels. These low dosage levels present new possibilities for manipulating the time of ovulation during a normal, not exogenous gonadotropin-stimulated cycle, without affecting the viability of the growing follicle. In case of inadequate follicular growth related to treatment with LHRH-antagonists, low dose and short term administration of gonadotrophin or other trophic compounds will compensate for these effects. Subsequently, by stopping the LHRH-antagonist treatment, it is possible to let the normal ovulation occur or to induce ovulation by exogenous manipulation, if necessary. Ovulation induction was induced by the administration of standard HCG or by administration of LHRH and/or LHRH agonistic analogs.

These described treatment alternatives are a departure from existing protocols, since they are possible only if preceded by treatment for LH-surge-control with an LHRH-antagonist. In animal and clinical studies with Cetrorelix it was shown that the responsiveness of the pituitary to LHRH or agonistic analogs is preserved under these conditions of treatment. Without this treatment, the pituitary cannot respond after agonistic pretreatment for LH-surge control due to receptor down-regulation. In addition, the possible use of ovulation inducing agents other than HCG results in a reduced incidence of ovarian hyperstimulation syndrome.

On the basis of the described results, for the first time it is possible to use normal, non-gonadotropin-stimulated cycles for assisted reproduction techniques, including sperm injections, by determining the time of ovulation by the duration and dose of Cetrorelix given. Especially in conjunction with the method of ICSI (Intra-Cytoplasmatic-Sperm-Injection) this antagonist-dependent treatment modality facilitates the inclusion of in-(sub-)fertile males into this kind of fertility treatment. Due to the direct injection of male gametes capable for fertilization, this method has a high success rate and hence, allows the harvest of only one follicle for fertilization. In addition, the use of LHRH-antagonists like Cetrorelix in the described manner relieves the patient from severe ovarian hyperstimulation and significantly reduces the costs of a treatment cycle.

LHRH-antagonists of the invention can be used in combination with assisted reproduction techniques, especially the extracorporal fertilization, e.g. the in-vitro fertilization and the sperm injection techniques.

Compounds with the desired LHRH-antagonistic activity include a LHRH-analog such as Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, Nal-Glu, 88-88, in particular Cetrorelix or a structure-truncated peptide with LHRH-antagonistic activity or a peptideomimetic with LHRH-antagonistic activity, for example D-23980 and D-24824, or a bicyclic (1-4. 4-10) LHRH analog with antagonistic activity.

LHRH-antagonists of the invention can be subcutaneously administered in dosage amounts of about 0.001-0.2 mg/kg.

Both dosing schedules demonstrate the prevention of any premature LH surge. After both posologies good fertilization rates have been obtained with good follicle and oocytes quality. Pregnancy rates are good after both treatments. To date, a total of 44 healthy babies are born following both treatments.

The single dose regimen requires only one single injection of 3 ml. This has to be regarded as being convenient for the patient. So far, duration of effect to prevent a premature LH surge is up to 6.5 days. After 3 days, monitoring of hormones is advisable in order to apply a second injection in case of a low responder to HMG with prolonged administration of HMG, and if an increase of LH values is seen.

The multiple dose schedule requires daily injections of 1 ml for 3 to 7 days, sometimes up to 10 or 14 days. This is not as convenient as a single or dual injection. On the other hand, regular monitoring of the hormones is not required and the application of HCG could even be extended if required in rare cases.

In summary, from a medical point of view, both treatments show comparable efficacy, safety and practicability, therefore each should have the possibility to decide upon the dosing schedule with respect to the situation observed in each single patient.

The results of a phase II clinical trial are shown in Table I. A total of 235 patients were treated.

No premature LH surge was seen in any patient undergoing COS/ART treated with either multiple doses of 0.25 mg or higher or a single dose of 3 mg or higher. During multiple dosing, the mean days of Cetrorelix application is 6 days. 25 babies were born by the end of May 1996 (7 following multiple doses; 18 following single/dual doses).

TABLE I Cetrorelix Development Controlled Ovarian Stimulation (COS/ART) Subj. Nos. Phase Dose/Day (mg) Posology (days)  14 II/proof concept  3 3-10  19 II/proof concept  1 3-10  11 II/proof concept  0.5 3-10  32 II/  0.5 3-7/14  30 dose finding/  0.25 min. effect. dose (28) minimal effective dose  0.10 no effect. dose  21 II/proof concept  5 1 or 2  18 II/proof concept  3 1 or 2  32 II/dose finding/  3 min. effective dose 1  30 minimal effective dose  2 no effect. Dose 1 SUM 235 71 pregnancies (30%) 44 healthy Phase II finished 16 pregnancies (ongoing) children The main advantages in controlled ovarian stimulation (COS/ART) with Cetrorelix are: 1. New therapeutic principle

a) Prevention of premature LH-surges

b) Uniform and continuous follicular synchronization

c) Uniform and continuous estradiol development

d) Very low LH-values for optimal follicular development

2. Short term treatment of 3 to 7 days to max 14 days

a) Short-term exposure during follicular development

b) Low medication exposure during follicular development

3. No flare-up but immediate hormonal response 4. No pretreatment for 14 to 21 days before start of HMG needed 5. Fits well into normal menstrual cycle with

a) No modification of physiological menstrual cycle pattern or

b) No hormonal withdrawal syndromes before stimulation

6. No or only ultrashort-term residual effects after ovulation induction 7. No residual effects during and following embryo transfer 8. No ovarian cyst formation before start of stimulation

9. Reduction of HMG.

Table II (flow chart) shows an example on a typical treatment start and duration of HMG and Cetrorelix in patients to undergo controlled ovarian superovulation for ART.

TABLE II Summary of assessments (Flow-chart) PERIOD: hMG² PERIOD d1 → until day of hCG: hCG⁴ apply if: Treatment/ Cetrorelix lead follicle: Investigations ≧20 mm φ or E₂ ≧ 1,200 pg/ml Post hMG PERIOD Parameters: pre hMG hMG days hMG day hMG cancel, if: ≧12 foll. OPU ET 6-8 Final day 1¹ d2-d5 d6 day² d7 ≧15 mm φ or days Docum.: Cycle day until the day E₂ ≧ 4,000 pg/ml after Day 20-25 2 or 3 of hCG (≧14,684 pmol/l) ET after ET Screening data X Pregnancy End of Trial Form X⁵ and Cetroreloix X X X Baby 0.25 mg s.c. daliy follow up hMG inj. (2/3/4+) X¹ 2 Amp X 2 Amp X 2+++ Amp X² 2+++ Amp X² 2+++ Amp Follow up: → hCG 10,000 IU X³ replacement l.m. injection cycles Ultrasound (USS) X X (X) optional (X) optional X X X Hormones: (hCG) X X¹ X X daily X⁷ 2-times: X X X X LH, FSH, E₂, P morning + just before hCG Lab(Hemat., X X X X clin. chem.) Luteal phase support X⁵ X⁶ → hCG or Progesterone. Tolerability/AE's X at every visit X¹ = 1st day (d 1) of hMG injection: after comfirmation (verified in the morning) of: menstrual bleeding; no pregnancy: hCG → neg. (≦10 IU/l); P ≦ 1 ng/ml (≦3.81 nmol/l); FSH ≦ 10 IU/l; no ovarian cyst (≧2 cm φ producing E₂ ≧ 50 pg/ml (≧185 pmol/l)). d1 of hMG = day 2 or 3 of menstrual cycle I X² = last day of hMG administration depends on follicle maturation (see X³). X³ = day of injection of 10.000 IU hCG; as soon as at least 1 follicle with a mean diameter of 20 mm, measured by ultrasound (USS) or E₂ ≧ 1 200 pg/ml (≧4 405 pmol/l), is observed. X⁴ = CAVE: In case of >12 follicles ≧ 15 mm φ or E₂ ≧ 4 000 pg/ml (≧14 684 pmol/l) during stilmulation period → no hCG injection I → Cycle cancellation I X⁵ = Luteal phase support to centre's rule: Either injections of hCG according to centre's rule or vagin. application of Progesterone (e.g. 3 × 200 mg/day) will be given accord. to centre's rule.I X⁶ = Must always be documented in any case of any premature study termination (e.g. in case of any Drop out). X⁷ = Blood samples for hormone determination on the day of hCG will be withdrawn 2 times (morning and just before hCG application) at hospital or oulsite. Ultrasound (USS): (X) will be undertaken according to centre's rule between day 6 of hMG until the day of hCG I USS has to be performed on the day of HCG!

EXAMPLE

238 patients were treated with Cetrorelix by subcutaneous injection of Cetrorelix Acetat-Lyophilisat.

134 patients were treated with multiple doses and 104 patients with single or dual doses. The multiple doses are 0.25 mg/day or higher. The single dose was 3 mg or higher. No premature LH surge was seen in any patient undergoing controlled ovarian superovulation for assisted reproduction technology (COS/ART) treated with these dosages. Multiple doses were applied for 3 to a maximum of 10 days dependent on follicular development.

As a result 71 pregnancies were obtained=30.0%

38 of 134 following the multiple does regimen=28.4%

33 of 104 following the single/dual dosage regimen=31.7%

Following treatment 44 babies were born that means 15 following multiple does and 29 following single/dual does. 16 pregnancies are still ongoing. FIG. 1 shows this in particular.

FIG. 1 shows an absolute prevention of any premature LH surge. Furthermore, FSH secretion is maintained at a natural level and therefore the individual estrogen development is not affected. 

1-37. (canceled)
 38. A method for obtaining the production of a fertilizable oocyte within a program of controlled ovarian stimulation for assisted reproduction techniques (COS/ART) consisting essentially of: (a) administering to a female human selected for controlled ovarian stimulation, a low dose of an LHRH-antagonist, wherein said low dose is sufficient to arrest a follicular growth in a first menstrual cycle, and wherein said low dose is administered during a luteal phase of a first menstrual cycle: (b) administering a single dose of luteinizing hormone (LH) and a single dose of follicle stimulating hormone (FSH) to induce follicle growth, wherein said luteinizing hormone and said follicle stimulating hormone are administered during a second menstrual cycle immediately following said first menstrual cycle, and (c) administering an amount of a luteinizing hormone releasing hormone (LHRH) antagonist selected from the group consisting of Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, Nal-Glu, 88-88, Cetrorelix, D23980, and D-24824, to prevent a premature LH surge, wherein the LHRH antagonist is administered as one or two, daily, 3 mg doses, beginning on menstrual cycle day 1 and continuing through day 10; wherein follicular growth occurs in the absence of a LH surge, a fertilizable oocyte is produced, ovulation occurs between day 9 and 20 of the menstruation cycle, and the dosage regimen of the LHRH antagonist is selected so as to suppress endogenous LH secretion, but does not suppress endogenous FSH secretion, which is maintained at a natural level and individual estrogen development is not affected.
 39. The method of claim 38, wherein step (a) comprises administering human menopausal gonadotropin (HMG) to induce follicle growth. 40-41. (canceled)
 42. The method of claim 38, wherein the LHRH antagonist is administered by subcutaneous injection.
 43. (canceled)
 44. The method of claim 38, wherein the LHRH antagonist is administered starting on cycle day 4 to
 8. 45. The method of claim 38, wherein the LHRH antagonist is administered starting on cycle day 6 to 10 and ovulation occurs between day 9-16 of the menstruation cycle.
 46. The method of claim 38, wherein ovulation occurs within 6.5 days following administration of a dose of the LHRH antagonist.
 47. (canceled)
 48. The method of claim 38, wherein ovulation is induced by administering a hormone or hormone agonist in order to induce ovulation.
 49. The method of claim 38, wherein ovulation is induced by administering a hormone or hormone agonist selected from the group consisting of native LH, recombinant LH, an LHRH agonist, and HCG.
 50. The method of claim 38, wherein the LHRH antagonist is Cetrorelix.
 51. A method for obtaining the production of a fertilizable oocyte within a program of COS/ART consisting essentially of: (a) administering to a female human selected for controlled ovarian stimulation, low dose of an LHRH-antagonist, wherein said low dose is sufficient to arrest a follicular growth in a first menstrual cycle, and wherein said low dose is administered during a luteal phase of a first menstrual cycle; (b) administering a single dose of human menopausal gonadotropin (HMG) to induce follicle growth, wherein said MGH is administered during a second menstrual cycle immediately following said first menstrual cycle, and (c) administering an amount of Cetrorelix to prevent a premature LH surge, wherein Cetrorelix is administered as one or two, daily, 3mg doses, beginning on menstrual cycle day 1 and continuing through day 10; wherein follicular growth occurs in the absence of a LH surge, a fertilizable oocyte is produced, ovulation occurs between day 9 and 20 of the menstruation cycle, and the dosage regimen of the Cetrorelix is selected so as to suppress endogenous LH secretion, but does not suppress endogenous FSH secretion, which is maintained at a natural level and individual estrogen development is not affected. 52-55. (canceled)
 56. The method of claim 51, wherein the Cetrorelix is administered starting on cycle day 4 to
 8. 57. The method of claim 51, wherein Cetrorelix is administered starting on cycle day 6 to 10 and ovulation occurs between day 9-16 of the menstruation cycle.
 58. The method of claim 51, wherein ovulation occurs within 6.5 days following administration of a single or second dose of Cetrorelix.
 59. (canceled)
 60. The method of claim 51, wherein ovulation is induced by administering a hormone or hormone agonist selected from the group consisting of native LH, recombinant LH, an LHRH agonist, and HCG.
 61. A method for obtaining the production of a fertilizable oocyte within a program of COS/ART comprising: (a) administering to a female human selected for controlled ovarian stimulation, a single dose of luteinizing hormone (LH) and a single dose follicle stimulating hormone (FSH) to induce follicle growth; and (b) administering an amount of an LHRH antagonist selected from the group consisting of Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, Nal-Glu, 88-88, Cetrorelix, D-23980, and D-24824 to prevent a premature LH surge; wherein the LHRH antagonist is administered as one or two, daily, 3 mg doses, beginning on menstrual cycle day 1 and continuing through day 10; wherein follicular growth occurs in the absence of a LH surge, a fertilizable oocyte is produced, wherein said amount of LHRH antagonist is sufficient to suppress LH, wherein said amount of LHRH antagonist does not suppress endogenous FSH secretion which is maintained at a natural level and individual estrogen development is not affected.
 62. The method of claim 61, wherein the dosage of LHRH antagonist is in the range of 2-6 mg per dose.
 63. The method of claim 61, wherein the dosage of LHRH antagonist is 3 mg per dose.
 64. (canceled)
 65. The method of claim 61, wherein the LHRH antagonist is administered by subcutaneous injection.
 66. (canceled)
 67. The method of claim 61, wherein the LHRH antagonist is administered starting on cycle day 4 to
 8. 68. The method of claim 61, wherein the LHRH antagonist is administered starting on cycle day 6 to 10 and ovulation occurs between day 9-16 of the menstruation cycle.
 69. The method of claim 61, wherein ovulation occurs within 6.5 days following administration of a single or second dose of the LHRH antagonist.
 70. The method of claim 61, wherein step (a) comprises administering human menopausal gonadotropin (HMG) to induce follicle growth.
 71. (canceled)
 72. The method of claim 61, wherein the LHRH antagonist is Cetrorelix.
 73. The method of claim 70, wherein the LHRH antagonist is Cetrorelix.
 74. The method of claim 73, wherein the dosage of Cetrorelix is in the range of 2-6 mg per dose.
 75. The method of claim 73, wherein the dosage of LHRH antagonist is 3 mg per dose. 76-77. (canceled)
 78. The method of claim 73, wherein the LHRH antagonist is administered starting on cycle day 4 to
 8. 79. The method of claim 73, wherein Cetrorelix is administered starting on cycle day 6 to 10 and ovulation occurs between day 9-16 of the menstruation cycle.
 80. The method of claim 73, wherein ovulation occurs within 6.5 days following administration of a dose of Cetrorelix. 81-82. (canceled)
 83. A method for obtaining the production of a fertilizable oocyte within a program of controlled ovarian stimulation for assisted reproduction techniques (COS/ART) comprising (a) administering a single dose of luteinizing hormone (LH) and a single dose of follicle stimulating hormone (FSH) to induce follicle growth, (b) administering an amount of an LHRH antagonist selected from the group consisting of Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, Nal-Glu, 88-88, Cetrorelix, D-23980, and D-24824 to prevent a premature LH surge, wherein the LHRH antagonist is administered in a dosage regimen of daily doses of 0.25 mg/day until ovulation, wherein the LHRH antagonist is administered daily beginning on menstruation cycle day 1 to 10, wherein the follicular growth occurs in the absence of a LH surge, a fertilizable oocyte is produced, ovulation occurs between day 9 and 20 of the menstruation cycle, and the LHRH antagonist is sufficient to suppress LH, while FSH secretion is maintained at a natural level and individual estrogen development is not affected.
 84. The method of claim 83, wherein the LHRH antagonist is administered by subcutaneous injection.
 85. (canceled)
 86. The method of claim 83, wherein the LHRH antagonist is administered starting cycle on day 4 to
 8. 87. The method of claim 83, wherein a daily dose of the LHRH antagonist is administered for 3 to 14 days.
 88. The method of claim 83, wherein a daily dose of the LHRH antagonist is administered for 3 to 7 days.
 89. (canceled)
 90. The method of claim 83, wherein ovulation is induced by administering a hormone or hormone agonist selected from the group consisting of native LH, recombinant LH, an LHRH agonist, and HCG.
 91. The method of claim 83, wherein the LHRH antagonist is Cetrorelix.
 92. A method for obtaining the production of a fertilizable oocyte within a program of COS/ART comprising: (a) administering to a female human selected for controlled ovarian stimulation, a single dose of human menopausal gonadotropin (HMG) to induce follicle growth, and; (b) administering an amount of Cetrorelix to prevent a premature LH surge, wherein Cetrorelix is subcutaneously administered in a dosage regimen of daily doses of 0.25 mg per day for multiple days; wherein follicular growth occurs in the absence of a LH surge, a fertilizable oocyte is produced, ovulation occurs between day 9 and 20 of the menstruation cycle, and the Cetrorelix is sufficient to suppress LH, while FSH secretion is maintained at a natural level and individual estrogen development is not affected.
 93. (canceled)
 94. The method of claim 92, wherein Cetrorelix is administered starting on cycle day 4 to
 8. 95. The method of claim 92, wherein a daily dose of Cetrorelix is administered for 3 to 14 days.
 96. The method of claim 92, wherein a daily dose of Cetrorelix is administered for 3 to 7 days.
 97. (canceled)
 98. The method of claim 92, wherein ovulation is induced by administering a hormone or hormone agonist selected from the group consisting of native LH, recombinant LH, an LHRH agonist, and HCG.
 99. A method for obtaining the production of a fertilizable oocyte within a program of controlled ovarian stimulation for assisted reproduction techniques (COS/ART) comprising (a) administering to a female human selected for controlled ovarian stimulation, a single dose of luteinizing hormone (LH) and a single dose of follicle stimulating hormone (FSH) to induce follicle growth; and (b) administering an amount of an LHRH antagonist selected from the group consisting of Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, Nal-Glu, 88-88, Cetrorelix, D-23980, and D-24824 to prevent a premature LH surge, wherein the LHRH antagonist is administered in a dosage regimen of daily doses of from 0.25 to 0.5 mg per day for multiple days; wherein follicular growth occurs in the absence of a LH surge, a fertilizable oocyte is produced, ovulation occurs normally between day 9 and 20 of the menstruation cycle and the LHRH antagonist is sufficient to suppress LH, while FSH secretion is maintained at a natural level and individual estrogen development is not affected.
 100. The method of claim 99, wherein the LHRH antagonist is administered by subcutaneous injection.
 101. (canceled)
 102. The method of claim 99, wherein the LHRH antagonist is administered starting cycle day 4 to
 8. 103. The method of claim 99, wherein a daily dose of the LHRH antagonist is administered for 3 to 14 days.
 104. The method of claim 99, wherein a daily dose of the LHRH antagonist is administered for 3 to 7 days.
 105. The method of claim 99, wherein step (a) comprises administering human menopausal gonadotropin (HMG) to induce follicle growth.
 106. (canceled)
 107. The method of claim 99, wherein the LHRH antagonist is Cetrorelix.
 108. The method of claim 105, wherein the LHRH antagonist is Cetrorelix.
 109. (canceled)
 110. The method of claim 108, wherein Cetrorelix is administered starting on cycle day 4 to
 8. 111. The method of claim 108, wherein a daily dose of Cetrorelix is administered for 3 to 14 days.
 112. The method of claim 108, wherein a daily dose of Cetrorelix is administered for 3 to 7 days.
 113. The method of claim 108, wherein ovulation occurs normally, without the administration of a hormone or hormone agonist to induce ovulation.
 114. The method of claim 108, wherein ovulation is induced by administering a hormone or hormone agonist selected from the group consisting of native LH, and recombinant LH.
 115. A method for obtaining the production of a fertilizable oocyte within a program of assisted reproduction techniques comprising in a female human selected for controlled ovarian stimulation,: (a) allowing normal follicular growth and development to proceed in the absence of stimulation by an exogenous gonadotropin; (b) administering an amount of an LHRH antagonist selected from the group consisting of Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, Nal-Glu, 88-88, Cetrorelix, D-23980, and D-24824, in a dosage regimen that prevents a premature LH surge, beginning on menstruation cycle day 1 to 10; wherein follicular growth and development proceeds in the absence of a LH surge and a fertilizable oocyte is produced, ovulation occurs between day 9 and 20 of the menstruation cycle, wherein said amount of said LHRH antagonist is sufficient to suppress LH, wherein said amount of said LHRH antagonist does not suppress endogenous FSH secretion, which is maintained at a natural level and individual estrogen development is not affected.
 116. The method of claim 115, wherein the LHRH antagonist is administered by subcutaneous injection.
 117. (canceled)
 118. The method of claim 115, wherein the LHRH antagonist is administered starting on cycle day 4 to
 8. 119. The method of claim 115, wherein the method is performed on a patient in whom follicular growth is inadequate due to previous treatment with an LHRH antagonist, and step (a) comprises allowing normal follicular growth and development to proceed in the absence of treatment of the patient with an LHRH antagonist and in the absence of stimulation by an exogenous gonadotropin.
 120. (canceled)
 121. (canceled)
 122. The method of claim 115, wherein ovulation is induced by administering a hormone or hormone agonist in order to induce ovulation.
 123. The method of claim 115, wherein ovulation is induced by administering a hormone or hormone agonist selected from the group consisting of native LH, recombinant LH, an LHRH agonist, and HCG. 124-125. (canceled)
 126. The method of claim 115, wherein the LHRH antagonist is Cetrorelix.
 127. The method of claim 115, wherein a fertilizable oocyte is produced within a program of extracorporeal fertilization by sperm injection.
 128. The method of claim 115, wherein a fertilizable oocyte is produced within a program of extracorporeal fertilization by in vitro fertilization.
 129. The method of claim 115, wherein the LHRH antagonist is administered in a single or dual dosage regimen of 1 to 10 mg per dose.
 130. The method of claim 129, wherein the dosage of LHRH antagonist is in the range of 2-6 mg per dose.
 131. The method of claim 129, wherein the LHRH antagonist is administered starting on cycle day 6 to 10 and ovulation occurs between day 9 to 16 of the menstruation cycle.
 132. The method of claim 129, wherein ovulation occurs within 6.5 days following administration of a single or second dose of the LHRH antagonist.
 133. The method of claim 129, wherein the LHRH antagonist is Cetrorelix.
 134. The method of claim 115, wherein the LHRH antagonist is administered in a dosage regimen of daily doses of from 0.25 to 0.5 mg/day for multiple days.
 135. The method of claim 134, wherein a daily dose of the LHRH antagonist is administered for 3 to 14 days.
 136. The method of claim 134, wherein a daily dose of the LHRH antagonist is administered for 3 to 7 days.
 137. The method of claim 135, wherein the LHRH antagonist is Cetrorelix.
 138. The method of claim 137, wherein the daily dose of Cetrorelix is 0.25 mg/day or 0.5 mg/day.
 139. The method of claim 83, wherein step (a) comprises administering human menopausal gonadotropin (HMG) to induce follicle growth.
 140. The method of claim 99, wherein the LHRH antagonist is Cetrorelix and the daily dose is 0.25 mg/day or 0.5 mg/day.
 141. The method of claim 108, wherein the daily dose of Cetrorelix is 0.25 mg/day or 0.5 mg/day. 